The haemostatic system is responsible for maintaining circulatory fluidity and for preventing haemorrhage in response to vascular attack. Physiological haemostasis is controlled by mechanisms that promote coagulation and the formation of fibrin and by those favouring its degradation or fibrinolysis. Excessive activation of coagulation or a defect of fibrinolysis lead to the formation of clots that obstruct the blood vessels (intravascular thrombosis), causing ischemia and necrosis. However, a general situation of hyper-fibrinolysis encourages the beginning of haemorrhages.
Hyperfibrinolytic states caused by congenital abnormalities or acquired in the coagulation-fibrinolysis system cause predisposition to important haemorrhagic complications. Such states have been associated with thrombolytic treatment as well as with surgery in organs containing a high amount of plasminogen activators, such as the prostate glands, uterus and lung. Also, disseminated intravascular coagulation (DIC), secondary to many medical and/or surgical processes, constitutes the prototype of the hyper-fibrinolytic state associated with massive haemorrhage in various organs.
In diseases with underlying haemorrhagic physiopathology caused by abnormal coagulation or increase in fibrinolysis, and aside from following transfusions of haemoderivatives, the pharmacological measures for treatment are often anti-fibrinolytic, but the treatment fails in approximately 30% of the cases.
Anti-fibrinolytic treatments seek to inhibit degradation of fibrin. The most common ones used in clinical treatment are synthetic analogues of lysine, such as epsilon-aminocaproic acid (EACA) and tranexamic acid (AMCHA), which compete with plasminogen for lysine binding sites, and aprotinin, that is a derivative of bovine lung with a broad protease inhibition spectrum.
These compounds have been shown to be effective in various clinical medical and surgical situations, such as intracraneal haemorrhage, surgery with elevated risk of haemorrhage and complications derived from thrombolytic treatment.
At a surgical level, the anti-fibrinolytic agents, in addition to reducing post-operative haemorrhage, can be an alternative to blood transfusion and other haemoderivatives in heart, liver and orthopaedic surgery. However, the use of these preparations has not become generalised, in part because there are insufficient studies demonstrating their effectiveness and also because they may increase the risk of thrombolytic complications (Mangano DT et al. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353-365).
For example, in hepatic surgery, fundamentally liver transplant, the use of anti-fibrinolytics such as aprotinin and AMCHA achieves a reduction in haemorrhagic complications, but can be associated with thrombolytic problems (de Boer MT et al. Minimizing blood loss in liver transplants: progress through research and evolution of techniques. Dig Surg 2005; 22: 265-275).
In intracranial haemorrhage, the anti-fibrinolytics have also not been incorporated into the clinical practice guides (You H et al. Hemostatic drug therapies for acute intracerebral haemorrhage. Cochrane Database Syst Rev 2006; CD005951). In the particular case of brain haemorrhage, primary or secondary to thrombolytic treatment, the use of recombinant factor VIIa is the only treatment that seems to have any beneficial effect in terms of the reduction of mortality (29% of patients receiving placebo compared to 18% of patients receiving factor VIIa) and of reduction of neurological sequelae (Mayer S. A., Brun N. C. et al.; “Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage”; N Engl J Med. 2005; 352: 777-785].
Disseminated intravascular coagulation (DIC) is another clinical condition that involves massive haemorrhage in which the administration of current anti-fibrinolytics is contraindicated as it encourages generalised thrombosis (Paramo JA. Coagulación intravascular diseminada. Med clin (Barc) 2006; 127: 785-9).
Thrombolysis with tPA or urokinase type plasminogen activators is one of the treatments of choice in acute heart attack and ischemic stroke but its use is associated with a high incidence of major haemorrhaging in up to 14% of cases and of intracranial haemorrhage in up to 4% of cases. In addition to treatment with haemoderivatives, the EACA or AMCHA type anti-fibrinolytics are indicated when there is excessive haemorrhaging, although their use can encourage thrombotic recurrence.
Excessive haemorrhaging after teeth extraction is one of the more common complications in patients with congenital coagulopathies such as haemophilia A. In these situations, the local use of anti-fibrinolytic and anti-haemorrhagic agents (e.g. tranexamic acid, desmopressin and Factor VII) contribute to the persistence of the clot and prevention of haemorrhage (Franchini M et al. Dental procedures in adult patients with hereditary bleeding disorders: 10 years experience in three Italian Hemophila Centers. Haemophilia 2005; 11: 504-509).
Anti-fibrinolytics are also the first line of treatment in women with menorrhagia associated with congenital coagulopathies in combination with hormonal therapy (Demers C et al. Gynaecological and obstetric management of women with inherited bleeding disorders. J Obstet Gynaecol 2005; 27: 707-732).
The application of topical treatment with fibrin gels has been an advancement in preventing haemorrhaging related to surgical wounds but its clinical use has still not been established (Gabay M. Absorbable hemostatic agents. Am J Health Syst Pharm. 2006; 63: 1244-53).
The intravenous or topical application of inhibitors of MMPs can restore haemostasis more quickly, reducing local haemorrhagic complications or those associated with tPA (Lapchak P A, Araujo D M. Reducing bleeding complications after thrombolytic therapy for stroke: clinical potential of metalloproteinase inhibitors and spin trap agents. CNS Drugs. 2001; 15 :819-29), encouraging the persistence of the clot, the repair and the healing of surgical wounds. Although this is a promising strategic option, most clinical trials with inhibitors of MMPs have failed; either because of the low doses used (efficacy vs toxicity) or due to observed side effects (musculoskeletal syndrome). It would be necessary to find more selective inhibitors that only block the molecular mechanisms associated with a specific MMP thereby avoiding adverse effects (Peterson JT. The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. Cardiovasc Res. 2006; 69: 677-687).
The purpose of the present invention is to provide alternative therapeutic compositions for anti-fibrinolytic treatment and for haemorrhagic complications that inhibit lysis of fibrin clots.